DESCRIPTION: The applicant's long term goal is to understand the molecular asis of synaptic function. Since many neurological diseases such as epilepsy, schizophrenia and depression, are caused by malfunctioning of the synapse, e understanding of synaptic mechanisms at the molecular level should provide insight into the basis of such diseases. Neurotransmitters released from the presynaptic terminals bind to specific receptors to open up specific channels localized on the postsynaptic membra . It has been a puzzle how the important synaptic components including recept s and channels become localized to specific sites of synaptic membranes. A specialized, cytoskeletal structure called postsynaptic density has been implicated in the mechanism of receptor/channel localization. The applican have isolated a gene encoding PSD-95, a prominent protein in the postsynapt density. Recently, evidence is accumulating that the PSD-95 protein is cru al for the localization of some receptors and channels at discrete sites of sy ptic membrane, and the localization process is mediated by interactions between specific domains of PSD-95 and receptor/channel proteins. The proposal is to study the roles of PSD-95 and its homologs in the receptor/channel localization. These noble PSD-95 homologs have tissue specificity distinct from PSD-95, suggesting that a family of PSD-95-like proteins may interact with tissue-specific proteins. The specific aims are s follows: (1) Tissue localization of mRNA and protein products of these gen will be examined by in situ hybridizations and immunocytochemistry, (2) Th GLGF domain of PSD-95 was shown to be important for the interaction with receptor/channel proteins. Transgenic mice will be generated to test wheth the overexpression of GLGF domain of PSD-95 might inhibit receptor clustering i vivo, (3) The SH3 domain of PSD-95 may interact with a different set of pro ins, but this possibility has not been tested. They will use a yeast two-hybrid system to search for such proteins, (4) GABAA beta receptor subunits contai a consensus sequence necessary for the interaction with PSD-95. It will be t ted whether this subunit can also be clustered by the PSD-95 protein.